Physiological Process Aging in C. elegans involves measurable declines in morphology, reproduction, and behavior. Understanding the cellular and molecular processes leading to senescence in this nematode began in the early 1980s with the targeted identification of mutants that extended life span (an AGE phenotype). These studies identified at least two key regulators of life span, DAF-2, an insulin/IGF receptor ortholog, and DAF-16, a Forkhead-related transcription factor. Since then many more genes and pathways involved in senescence have been identified. Almost all of these genes play important roles in cellular and organismal-level processes other than aging, such as dauer formation, stress response, feeding, and chemosensation. c18 d3a daf-18 functions upstream to akt-1 and akt-2 daf-18 acts downstream of age-1 ee0 e61 age-1 encodes a homologue of mammalian phosphatidylinositol-3-OH kinase catalytic subunit. f57 insulin/IGF-1 pathway can diverge to regulate the timing of reproduction independently of longevity (Dillin et al., 2002a). eef d91 d91 a81 d91 a81 PRMT-1 specifically methylates the C terminus of the forkhead domain (FH-C) in DAF-16 blocking binding to 14-3-3 protein. DAF-16 is predominantly localized in the cytoplasm as a result of inhibitory phosphorylation of Ser/Thr residues by the AKT and SGK kinases. T242 is an AKT-mediated phosphorylation site in DAF-16 a47 b69 ed9 a81 DAF-16 binds to JNK-1. JNK-1 binds and phosphorylates DAF-16. f8b a47 b69 f8b f8b ed9 DAF-16 bound directly to PRMT-1 in in vitro pulldown assays , HA-PRMT-1 was coimmunoprecipitated with FLAG-DAF-16 only when the both proteins were coexpressed. ed9 ee4 age-1 encodes a homologue of mammalian phosphatidylinositol-3-OH kinase catalytic subunit. RLE-1 physically interacts with DAF-16. RLE-1 C terminus is required for the interaction of RLE-1 with DAF-16. ee4 SMK-1 was temporally and spatially colocalized with active DAF-16. smk-1 RNAi does not cause a general sickness in long-lived animals but rather specifically affects IIS-regulated life span. DAF-16 and SMK-1 do not directly or indirectly regulate expression or localization of one another. SMK-1 specifies the longevity function of DAF-16 by affecting the efficiency of transcription of DAF-16 target genes involved in oxidative and UV stress response and innate immunity but is not required for DAF-16 regulation of heat-stress-response genes. e0e DAF-16 is predominantly localized in the cytoplasm as a result of inhibitory phosphorylation of Ser/Thr residues by the AKT and SGK kinases. Reduced smk-1 resulted in increased expression of daf-15 mRNA, suggesting that SMK-1 is required for the transcriptional repressor activity of DAF-16 e0e PRMT-1 specifically methylates the C terminus of the forkhead domain (FH-C) in DAF-16 blocking binding to 14-3-3 protein. DAF-16 is predominantly localized in the cytoplasm as a result of inhibitory phosphorylation of Ser/Thr residues by the AKT and SGK kinases. T242 is an AKT-mediated phosphorylation site in DAF-16 a47 b69 ed9 a81 T242 Phosphorylation JNK-1 binds and phosphorylates DAF-16 ee0 AGE-1 works in a parallel pathway downstream of daf-2 signaling. d91 d91 an activating mutation in akt-1 or increased dosage of akt-1(+) can bypass the normal requirement for AGE-1 PI3K signaling but still partially depends on DAF-2 signaling, showing that akt-1 is the major output of PI3K signaling but not the only output of the DAF-2 insulinlike receptor a81 d91 a81 ed9 JKK-1 is the upstream kinase of JNK-1 and phosphorylation of JNK-1 is required for lifespan extension. f8b AKT phosphorylates DAF-16 at site T242, promoting its binding to 14-3-3. ed9 PRMT-1 methylates DAF-16, thereby blocking its phosphorylation by AKT. PRMT-1 blocks AKT-mediated phosphorylation of DAF-16 at T242 and thereby inhibits its 14-3-3 binding and cytoplasmic retention in C. elegans. 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